The present invention relates to indole derivatives.
More specifically, the present invention relates to indole derivatives represented by formula (I): 
(wherein all symbols have the same meanings as described below), a process for the preparation of the same and use thereof.
Prostaglandin D (hereinafter referred to as xe2x80x9cPGDxe2x80x9d) are known as a metabolite in the arachidonic acid cascade, and are known to have effects of bronchoconstriction, vasodilatation or vasoconstriction and platelet aggregation inhibition. PGD is considered to be produced from mast cells, and the increase of PGD concentration has been recognized among systemic mastocytosis patients (New Eng. J. Med., 303, 1400-1404 (1980)). Also, PGD is considered to relate to neuro activities, especially, sleep and hormone secretion. Furthermore, there are reports suggesting participations in platelet aggregation, glycogen metabolism, ocular tension adjustment and the like.
PGD shows its effects by binding to a DP receptor which is a receptor thereof. A DP receptor antagonist binds to and is antagonistic to its receptor so that it can inhibit the function of PGD. Accordingly, it is considered to be useful for the prevention and/or treatment of diseases, for example, allergic diseases such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, etc.; systemic mastocytosis; disorders due to systemic mastocyte activation; anaphylactic shock; bronchoconstriction; urticaria; eczema; allergic bronchopulmonary aspergillosis; inflammatory paranasal sinus; nasal polyp; hypersensitive angitis; eosinophilia; contact dermatitis; diseases accompanied with itching, such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.; secondary diseases caused by behaviors (scratching behaviors, beating, etc.), such as cataract, retinal detachment, inflammation, infection, sleep disorder, etc.; inflammation; chronic obstructive pulmonary disease; ischemic reperfusion disorder; cerebrovascular disorder; pleuritis complicated by rheumatoid arthritis; ulcerative colitis; and the like. Moreover, it is considered to relate to sleeping and platelet aggregation and to be useful for these diseases.
Some DP receptor antagonists are known until now, and BW-A868C represented by formula (A) is considered to be the most selective: 
Also, recently, DP receptor antagonists which are thromboxane derivatives have been published in WO 98/25915, WO 98/25919, WO 97/00853, WO 98/15502 and the like.
On the other hand, as a compound similar to the compound of the present invention, an indole compound represented by formula (B) is known as a synthetic intermediate (J. Heterocyclic Chem., 19, 1195 (1982)). 
The present inventors intensively studied to find a compound which specifically binds to DP receptor and show an antagonistic activity and found that the object could be attained by indole derivatives represented by formula (I), and thus the present invention has been completed.
That is, the present invention relates to an indole derivative represented by formula (I): 
wherein R1 represents hydroxy, C1-6 alkoxy, or NR8R9, in which R8 and R9 each independently represents a hydrogen atom, C1-6 alkyl, or SO2R13, in which R13 represents C1-6 alkyl, a C3-15 saturated or unsaturated carbocyclic ring or a 4- to 15-membered heterocyclic ring containing 1 to 5 nitrogen atom(s), sulfur atom(s) and/or oxygen atom(s);
R2 represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, a halogen atom, amino, trihalomethyl, cyano, hydroxy, benzyl, or 4-methoxybenzyl;
R3 represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, a halogen atom, trihalomethyl, cyano, or hydroxy;
R4 and R5 each independently represents a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, C2-6 alkoxyalkyl, a halogen atom, nitro, amino, trihalomethyl, cyano, or hydroxy;
D represents a single bond, C1-6 alkylene, C2-6 alkenylene, or C1-6 oxyalkylene;
in -G-R6,
1) G represents a single bond, C1-6 alkylene which may be substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s), C2-6 alkenylene which may be substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s), in which the alkylene and the alkenylene may be substituted with hydroxy or C1-4 alkoxy, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, or diazo;
R6 represents a C3-15 saturated or unsaturated carbocyclic ring, or a 4- to 15-membered heterocyclic ring containing 1 to 5 nitrogen atom(s), sulfur atom(s) and/or oxygen atom(s), in which the ring may be substituted with 1 to 5 substituent(s) selected from C1-6 alkyl, C1-10 alkoxy, C2-6 alkoxyalkyl, a halogen atom, hydroxy, trihalomethyl, nitro, amino, phenyl, phenoxy, oxo, C2-6 acyl, C1-6 alkanesulfonyl and cyano,
2) G and R6 are taken together to represent
(i) C1-15 alkyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s);
(ii) C2-15 alkenyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s); or
(iii) C2-15 alkynyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s),
in which the alkyl, the alkenyl and the alkynyl may be substituted with 1 to 12 substituent(s) selected from C1-6 alkoxy, a halogen atom, hydroxy, cyano, oxo and NR11R12, in which R11 and R12 each independently represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, phenyl, benzoyl, naphthyl, phenyl substituted with C1-6 alkyl, or C1-6 alkyl substituted with phenyl or cyano;
n represents 1 to 3;
m represents 1 to 3;
i represents 1 to 4; and
 represents a single bond or a double bond, or a non-toxic salt thereof;
(2) a process for the preparation thereof;
(3) a pharmaceutical agent comprising it as an active ingredient; and
(4) 2-methylindole-4-acetic acid which is a novel synthetic intermediate.
In formula (I), the C1-6 alkyl represented by R2, R3, R4, R5, R6, R8, R9, R11, R12 or R13 includes, methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof.
In formula (I), the C1-6 alkoxy represented by R1, R2, R3, R4 or R5 includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, and isomers thereof.
In formula (I), the C1-10 alkoxy represented by R6 includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and isomers thereof.
In formula (I), the C1-15 alkyl represented by G and R6 taken together includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, and isomers thereof.
In formula (I), the C1-15 alkyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R6 taken together represents the above alkyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-15 alkenyl represented by G and R6 which are taken together includes vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pehtadecenyl, and isomers thereof.
In formula (I), the C2-15 alkenyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R6 which are taken together represents the above alkenyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-15 alkynyl represented by G and R6 which are taken together includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, and isomers thereof.
In formula (I), the C2-15 alkynyl which may be substituted with 1 to 5 oxygen atom(s) and/or sulfur atom(s) represented by G and R6 which are taken together represents the above alkynyl in which any 1 to 5 carbon atom(s) are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-6 alkoxyalkyl represented by R2, R4, R5 or R6 includes methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propyloxymethyl, propyloxyethyl, propyloxypropyl, butyloxymethyl, butyloxyethyl, pentyloxymethyl, and isomers thereof.
In formula (I), the C1-6 alkylene represented by D or G includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, and isomers thereof.
In formula (I), the C2-6 alkenylene represented by D includes vinylene, propenylene, butenylene, pentenylene, hexenylene, and isomers thereof.
In formula (I), the C1-6 oxyalkylene represented by D includes oxymethylene, oxyethylene, oxybutylene, oxypehtylene, oxyhexylene, and isomers thereof.
In formula (I), the C1-6 alkylene which may by substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s) represented by G includes the above C1-6 alkylene in which any carbon atom(s) is/are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-6 alkenylene which may by substituted with 1 to 2 oxygen atom(s) and/or sulfur atom(s) represented by G includes the above C2-6 alkenylene in which any saturated carbon atom(s) is/are substituted with an oxygen atom(s) and/or a sulfur atom(s).
In formula (I), the C2-6 alkenyl represented by R11 or R12 includes vinyl, propenyl, butenyl, pentenyl, hexenyl, and isomers thereof.
In formula (I), the halogen atom represented by R2, R3, R4, R5 or R6 includes fluorine, chlorine, bromine, and iodine.
In formula (I), the trihalomethyl represented by R2, R3, R4, R5 or R6 includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
In formula (I), the C1-10 alkoxy represented by R10 includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and isomers thereof.
In formula (I), the C2-6 acyl represented by R6 includes acetyl, propionyl, butyly, valeryl, hexanoyl, and isomers thereof.
In formula (I), the C1-6 alkanesulfonyl represented by R6 includes methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, and isomers thereof.
In formula (I), the C3-15 carbocyclic ring represented by R6 or R13 includes monocyclic, bicyclic or tricyclic unsaturated or saturated carbocyclic ring having carbon numbers of 3 to 15.
Examples of the monocyclic, bicyclic or tricyclic unsaturated or saturated carbocyclic ring having carbon numbers of 3 to 15 include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, heptalene, biphenylene, fluorene, phenanthrene, anthracene, dihydroanthracene, tetrahydroanthracene, perhydroanthracene, fluorene, dihydrofluorene, tetrahydrofluorene, perhydrofluorene, norbornane, norpinane, norbornane, norbornene, norpinane, norpinene rings and the like.
In formula (I), the 4- to 15-membered heterocyclic ring containing 1 to 5 nitrogen atom(s), sulfur atom(s) and/or oxygen atom(s) represented by R6 or R13 is unsaturated or saturated, and examples includes the following formulas: 
In formula (I), R1 is preferably hydroxy, C1-6 alkyl or NR8R9, and more preferably hydroxy or C1-8 alkyl.
In formula (I), R2 is preferably a hydrogen atom, C1-6 alkyl or C1-6 alkoxyalkyl, and more preferably a hydrogen atom, C1-2 alkyl or C1-2 alkoxyalkyl.
In formula (I), R3 is preferably a hydrogen atom or C1-6 alkyl.
In formula (I), R4 is preferably a hydrogen atom or C1-6 alkyl, and more preferably a hydrogen atom or C1-2 alkyl.
In formula (I), R5 is preferably a hydrogen atom or C1-6 alkyl, and more preferably a hydrogen atom or C1-2 alkyl.
In formula (I), D is preferably a single bond or C1-6 alkylene, and more preferably a single bond or C1-2 alkylene.
In formula (I), G is preferably C1-6 alkylene which may be substituted with 1 or 2 oxygen atom(s), and more preferably C1-2 alkylene which may be substituted with one oxygen atom.
In formula (I), R6 is preferably a C5-10 carbocyclic ring or a monocyclic or bicyclic 5- to 10-membered heterocyclic ring containing 1 to 3 nitrogen, oxygen and/or sulfur atom(s), which each may be substituted, and more preferably a bicyclic 9- or 10-membered heterocyclic ring containing 1 to 3 nitrogen, oxygen and/or sulfur atoms(s) which may be substituted.
Also, G and R6 are preferably taken together to represent C1-10 alkyl which may be substituted with 1 to 4 oxygen and/or sulfur atom(s), C2-10 alkenyl which may be substituted with 1 to 4 oxygen and/or sulfur atom(s), or C2-10 alkynyl which may be substituted with 1 to 4 oxygen and/or sulfur atom(s).
Unless otherwise indicated, all isomers are included in the present invention. For example, the alkyl, alkenyl and alkynyl groups and alkylene group include straight-chain groups and branched-chain groups. In addition, isomers in double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, xcex1-, xcex2-isomer, enantiomer, diastereomer), optically active isomers having optical rotation (D-, L-, d-, I-isomer), polar compounds separated by chromatography (high polar compound, low polar compound), equilibrium compounds, mixtures thereof at arbitrary ratios and racemic mixtures are included in the present invention.
Among the compounds of the present invention represented by formula (I), preferred compounds are compounds shown in Examples, compounds represented by formula (I-A1): 
(wherein when R6 represents a ring, R61 represents a substituent of the ring; p is 0 or an integer of 1 to 3; and other symbols have the same meanings as described above), formula (I-A2): 
(wherein all symbols have the same meanings as described above), formula (I-A3): 
(wherein all symbols have the same meanings as described above), formula (I-A4): 
(wherein all symbols have the same meanings as described above), formula (I-A5): 
(wherein all symbols have the same meanings as described above), formula (I-A6): 
(wherein all symbols have the same meanings as described above), formula (I-A7): 
(wherein all symbols have the same meanings as described above), formula (I-A8): 
(wherein all symbols have the same meanings as described above), formula (I-A9): 
(wherein all symbols have the same meanings as described above), formula (I-A10): 
(wherein all symbols have the same meanings as described above), formula (I-B1)1
(wherein all symbols have the same meanings as described above), formula (I-B2): 
(wherein all symbols have the same meanings as described above), formula (I-B3): 
(wherein all symbols have the same meanings as described above), formula (I-B4): 
(wherein all symbols have the same meanings as described above), formula (I-B5): 
(wherein all symbols have the same meanings as described above), formula (I-B6): 
(wherein all symbols have the same meanings as described above), formula (I-B7): 
(wherein all symbols have the same meanings as described above), formula (I-B8): 
(wherein all symbols have the same meanings as described above), formula (I-C1): 
(wherein all symbols have the same meanings as described above), formula (I-C2): 
(wherein all symbols have the same meanings as described above), formula (I-C3): 
(wherein all symbols have the same meanings as described above), formula (I-C4): 
(wherein all symbols have the same meanings as described above), formula (I-C5): 
(wherein all symbols have the same meanings as described above), formula (I-C6): 
(wherein all symbols have the same meanings as described above), formula (I-C7): 
(wherein all symbols have the same meanings as described above), formula 
(wherein all symbols have the same meanings as described above), formula (I-C9): 
(wherein all symbols have the same meanings as described above), formula (I-C10): 
(wherein all symbols have the same meanings as described above), formula (I-C11): 
(wherein all symbols have the same meanings as described above), formula (I-C12) 
(wherein all symbols have the same meanings as described above), formula (I-C13) 
(wherein all symbols have the same meanings as described above), formula (I-C14) 
(wherein all symbols have the same meanings as described above), formula (I-C15): 
(wherein all symbols have the same meanings as described above), formula (I-D1): 
(wherein all symbols have the same meanings as described above), formula (I-D2): 
(wherein all symbols have the same meanings as described above), formula (I-D3): 
(wherein all symbols have the same meanings as described above), formula (I-D4): 
(wherein all symbols have the same meanings as described above), formula (I-D5): 
(wherein all symbols have the same meanings as described above), formula (I-D6): 
(wherein all symbols have the same meanings as described above), formula (I-D7): 
(wherein all symbols have the same meanings as described above), formula (I-D8): 
(wherein all symbols have the same meanings as described above), formula (I-D9): 
(wherein all symbols have the same meanings as described above), formula (I-E1): 
(wherein all symbols have the same meanings as described above), formula (I-E2): 
(wherein all symbols have the same meanings as described above), formula (I-E3): 
(wherein all symbols have the same meanings as described above), formula (I-E4): 
(wherein all symbols have the same meanings as described above), formula (I-E5): 
(wherein all symbols have the same meanings as described above), formula (I-E6): 
(wherein all symbols have the same meanings as described above), formula (I-E7): 
(wherein all symbols have the same meanings as described above), formula (I-E8): 
(wherein all symbols have the same meanings as described above), formula (I-E9): 
(wherein all symbols have the same meanings as described above), formula (I-E10): 
(wherein all symbols have the same meanings as described above), formula (I-E12): 
(wherein all symbols have the same meanings as described above), formula (I-E12): 
(wherein all symbols have the same meanings as described above), formula (I-E13): 
(wherein all symbols have the same meanings as described above), formula (I-E14): 
(wherein all symbols have the same meanings as described above), formula (I-E15): 
(wherein all symbols have the same meanings as described above), formula (I-E16): 
(wherein all symbols have the same meanings as described above), formula (I-E17): 
(wherein all symbols have the same meanings as described above), formula (I-E18): 
(wherein all symbols have the same meanings as described above), formula (I-E19): 
(wherein all symbols have the same meanings as described above), formula (I-E20): 
(wherein all symbols have the same meanings as described above), formula (I-E21) 
(wherein all symbols have the same meanings as described above), formula (I-E22) 
(wherein all symbols have the same meanings as described above), formula (I-E23): 
(wherein all symbols have the same meanings as described above), formula (I-F1): 
(wherein all symbols have the same meanings as described above), formula (I-F2): 
(wherein all symbols have the same meanings as described above), formula (I-F3): 
(wherein all symbols have the same meanings as described above), formula (I-F4): 
(wherein all symbols have the same meanings as described above), formula (I-F5): 
(wherein all symbols have the same meanings as described above), formula (I-F6): 
(wherein all symbols have the same meanings as described above), formula (I-F7): 
(wherein all symbols have the same meanings as described above), formula (I-F8): 
(wherein all symbols have the same meanings as described above), formula (I-F9): 
(wherein all symbols have the same meanings as described above), formula (I-F10): 
(wherein all symbols have the same meanings as described above), formula (I-F11): 
(wherein all symbols have the same meanings as described above), formula (I-F12): 
(wherein all symbols have the same meanings as described above), formula (I-F13): 
(wherein all symbols have the same meanings as described above), formula (I-F14): 
(wherein all symbols have the same meanings as described above), compounds shown in Tables 1 to 5, and non-toxic salts of the compounds.
Salt:
The compound of the present invention represented by formula (I) can be converted into a corresponding salt by known methods. The salt is preferably a non-toxic and water-soluble salt. Appropriate salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals, ammonium salts (tetramethylammonium, tetrabutylammonium salts, etc.), and pharmaceutically acceptable organic amines (triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, etc.).
The compound of the present invention represented by formula (I) and a salt thereof can also be converted into a hydrate by known methods.
Processes for the Preparation of the Compound of the Present Invention:
The compound of the present invention represented by formula (I) can be prepared by the following processes and the processes shown in Examples.
(a) Among the compounds represented by formula (I), a compound wherein R1 is hydroxy, i.e., a compound represented by formula (Ia): 
(wherein all symbols have the same meanings as described above) can be prepared by subjecting to a deprotection reaction a compound represented by formula (IV): 
(wherein R20 is an allyl or benzyl group; and other symbols have the same meanings as described above).
The deprotection reaction of ally ester or benzyl ester is known, for example, it is carried out in an organic solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, etc.) at xe2x88x9210 to 90xc2x0 C. by
1) using tetrakis(triphenylphosphine)palladium and morpholine, or
2) using palladium carbon, palladium, platinum, sponge nickel (trade name: Raney Nickel), etc. under hydrogen atmosphere.
(b) Among the compounds represented by formula (I), a compound wherein R1 is C1-6 alkoxy (wherein all symbols have the same meanings as described above), i.e., a compound represented by formula (Ib): 
(wherein R10 represents C1-6 alkyl; and other all symbols have the same meanings as described above) can be prepared by subjecting to an esterification reaction a compound represented by formula (Ia) with a compound represented by formula:
R10xe2x80x94OHxe2x80x83xe2x80x83(III) 
(wherein all symbols have the same meanings as described above), followed by optionally a deprotection reaction.
The esterification reaction is known, for example, it is carried out in an inert organic solvent (tetrahydrofuran, methylene chloride, benzene, acetone, acetonitrile, a mixture thereof, etc.) in the presence or absence of a tertiary amine (dimethylaminopyridine, pyridine, triethylamine, etc.) using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) or acid halide (oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.) at 0 to 50xc2x0 C.
(c) Among the compounds represented by formula (I), a compound wherein R1 is xe2x80x94NR8R9 (wherein all symbols have the same meanings as described above), i.e., a compound represented by formula (Ic): 
(wherein all symbols have the same meanings as described above) can be prepared by subjecting to an amidation reaction a compound represented by formula (Ia) with a compound represented by formula:
HNR10R11xe2x80x83xe2x80x83(II) 
(wherein all symbols have the same meanings as described above), followed by optionally a deprotection reaction.
The amidation reaction is known, for example, it is carried out in an inert organic solvent (tetrahydrofuran, methylene chloride, benzene, acetone, acetonitrile, a mixture thereof, etc.) in the presence or absence of a tertiary amine (dimethylaminopyridine, pyridine, triethylamine, etc.) using a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), etc.) or acid halide (oxalyl chloride, thionyl chloride, phosphorus oxychloride, etc.) at of 0 to 50xc2x0 C.
The compound represented by formula (IV) can prepared by subjecting to a compound represented by formula (V): 
(wherein R21, R31 and R41 have the same meanings as R2, R3 and R4, respectively, and when they represent an amino group or a hydroxy group, they are protected with a protecting group; and other symbols have the same meanings as described above) with a compound represented by formula (VI): 
(wherein R51 has the same meaning as R5, and when it represents an amino group or a hydroxy group, it is protected with a protecting group; and G1 and R61 have the same meanings as G and R6, respectively, and when they contains an amino group or a hydroxy group, it is protected with a protecting group), followed by optionally a deprotection reaction. The amidation reaction can be carried out by the above method.
The compounds represented by formula (II), (III), (V) and (VI) are known per se or can be prepared by known methods.
Among the compounds represented by formula (Ia), a compound wherein D is alkylene can be prepared by reducing a compound represented by formula (Ia), or can be prepared by increasing the carbon of the alkylene part.
In each reaction in the present specification, reaction products can be purified by conventional purification techniques, e.g., by distillation under atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing, recrystallization or the like. Purification can be carried out after each reaction or after some reactions.
Pharmacological Activities:
The compound of the present invention represented by formula (I) potently binds to a DP receptor and show an antagonistic activity. For example, in a laboratory test, such effects were confirmed by the following receptor binding test using prostanoid receptor-expressing cells.
(i) Receptor Binding Test Using Prostanoid DP Receptor-Expressing Cells
CHO cells expressing a mouse DP receptor was prepared according to the method of Hirata et al. (Proc. Natl. Acad. Sci., 91, 11192-11196 (1994)) and used as a membrane standard.
A reaction solution (200 xcexcL) containing the prepared membrane standard (30-166 xcexcg) and 3H-PGD2 was incubated at room temperature for 20 minutes. The reaction was stopped with an ice-cold buffer (1 mL) and the binding 3H-PGD2 was trapped in on a glass filter by immediate aspiration-filtration under a reduced pressure, and its binding radioactivity was measured using a liquid scintillation counter.
A Kd value and a Bmax value were obtained from Scatchard plots (Ann. N.Y. Acad. Sci., 51, 660 (1949)). Non-specific binding was obtained as the binding radioactivity in the presence of unlabeled PGD2 at an excess amount (10 xcexcmol/L). 3H-PGD2 binding inhibition by the compound of the present invention was measured by adding 3H-PGD2 (2.5 mmol/L) and the compound of the present invention as various concentrations. Also, the following buffers were used for the reactions.
Incubation buffer:
HEPES-NaOH (25 mmol/L, pH 7.4)
EDTA (1 mmol/L)
MgCl2 (5 mmol/L)
MnCl2 (10 mmol/L)
Buffer for washing:
Tris-HCl (10 mmol/L, pH 7.5)
NaCl (0.1 mol/L)
Bovine serum albumin (0.01%)
The dissociation constant (Ki) (xcexcmol/L) of each compound was obtained by the following equation.
Ki=IC50/(1+([L]*/Kd))
[L*]: Concentration of radioligand
The results are shown in Table 6.
As shown in the above results, it is apparent that the compound of the present invention potently binds to a DP receptor.
(ii) DP Antagonistic Activity Assay Using Prostanoid DP Receptor-Expressing Cells
CHO cells expressing a mouse DP receptor were prepared according to the method of Nishigaki et al. (FEBS lett., 364, 339-341 (1995)), inoculated onto a 24-well microplate at 105 cells/well, followed by culturing for 2 days, and used for the assay. Each well was washed with 500 xcexcL of MEM (minimum essential medium), and 450 xcexcL of assay medium (MEM containing 1 mmol/L IBMX and 0.1 or 1% BSA), followed by incubation at 37xc2x0 C. for 10 minutes. Then, an assay medium (50 xcexcL) containing PGD2 alone or PGD2 with a test compound was added thereto to start the reaction, and after the reaction at 37xc2x0 C. for 10 minutes, 500 xcexcL of ice-cold trichloroacetatic acid (TCA) (10% w/v) was added thereto to stop the reaction. The reaction solution was frozen once (xe2x88x9280xc2x0 C.) and thawed, and cells were peeled using a scraper, followed by centrifugation at 13,000 rpm for 3 minutes. The cAMP concentration was measured with a cAMP assay kit using the resulting supernatant. That is, [125I]-cAMP assay kit buffer was added to 125 xcexcL of the supernatant to give a total amount of 500 xcexcL, and the resulting mixture was mixed with 1 mL of a chloroform solution of 0.5 mol/L tri-n-octylamine. Trichloro acetic acid (TCA) was extracted to the chloroform layer and removed, the cAMP amount in a sample was determined using the aqueous layer as the sample according to the method described in the [125I]cAMP assay kit.
Also, with regard to the antagonistic activity (IC50) of the test compound, the IC50 value was calculated as an inhibition rate based on the reaction at 100 nM which was a concentration showing submaximal cAMP production by PGD2 alone.
As shown in the above results, it is apparent that the compound of the present invention has an antagonistic activity against a DP receptor.
Toxicity:
The toxicity of the compound represented by formula (I) of the present invention is very low so that it is confirmed that the compound is sufficiently safe for using as a pharmaceutical.
Application to Pharmaceuticals:
Since the compound of the present invention represented by formula (I) bind to and is antagonistic to a DP receptor, it is considered that the compound is useful for the prevention and/or treatment of diseases, for example, allergic diseases such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, etc.; systemic mastocytosis; disorders due to systemic mastocyte activation; anaphylactic shock; bronchoconstriction; urticaria; eczema; allergic bronchopulmonary aspergillosis; inflammatory paranasal sinus; nasal polyp; hypersensitive angitis; eosinophilia; contact dermatitis; diseases accompanied with itching, such as atopic dermatitis, urticaria, allergic conjunctivitis, allergic rhinitis, contact dermatitis, etc.; secondary diseases caused by behaviors (scratching behaviors, beating, etc.), such as cataract, retinal detachment, inflammation, infection, sleep disorder, etc.; inflammation; chronic obstructive pulmonary disease; ischemic reperfusion disorder; cerebrovascular disorder; pleuritis complicated by rheumatoid arthritis; ulcerative colitis; and the like. Moreover, the compound is considered to relate to sleeping and platelet aggregation and to be useful for these diseases.
Among the compounds of the present invention represented by formula (I), one having a weak binding activity to a compound other than a DP receptor would be used as a pharmaceutical having less side effects because it does not show other activity.
When the compound represented by formula (I) of the present invention, a non-toxic salt or a cyclodextrin inclusion compound thereof is normally administered systemically or topically and orally or parenterally.
The dosages are determined depending on age, body weight, symptom, therapeutic effect, administration route, duration of the treatment and the like. Generally, 1 xcexcg to 100 mg per adult is orally administered once to several times per day, or 0.1 xcexcg to 10 mg per adult is parenterally administered (preferably by intravenous administration) once to several times per day, or continuously administered from vein for 1 to 24 hours per day.
Since the dose changes depending on various conditions as described above, there are cases in which doses lower than or greater than the above ranges may be used.
The compounds of the present invention may be administered in the form of solid compositions, liquid compositions or other compositions for oral administration, and injections, liniments, suppositories and the like for parenteral administration.
Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, granules and the like.
Capsules include hard capsules and soft capsules.
In such solid compositions, one or more active compound(s) is/are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or magnesium metasilicate aluminate.
The compositions may also contain additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate, disintegrating agents such as cellulose calcium glycolate, and assisting agents for dissolving such as glutamic acid, asparatic acid according to usual methods. The tablets or pills may, if desired, be coated with film of gastric- or enteric-coating agents such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate, or be coated with two or more films. Furthermore, capsules of absorbable materials such as gelatin are included
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, syrups and elixirs. In such compositions, one or more active compound(s) is/are dissolved, suspended or emulsified in an inert diluent commonly used (e.g., purified water, ethanol). Furthermore, such liquid compositions may also contain wetting agents or suspending agents, emulsifying agents, sweetening agents, flavoring agents, perfuming agents, and preserving agents.
Other compositions for oral administration include sprays containing one or more active compound(s) which are prepared by known methods. Spray compositions may contain stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic solutions such as sodium chloride, sodium citrate or citric acid, other than inert diluents. The process for preparing the sprays are described in U.S. Pat. Nos. 2,868,691 and 3,095,355.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions or suspensions include, for example, distilled water for injection and a physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSORBATE80 (registered trade mark), and the like.
Such compositions may contain additional diluents such as preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, assisting agents such as assistant agents for dissolving (e.g., glutamic acid, aspartic acid). They may be sterilized by filtration through a bacteria-retaining filter, or incorporation or irradiation of a sterilizing agent. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, endemic liniments, ointments, suppositories for intrarectal administration and pessaries for intravaginal administration containing one or more active compound(s) which can be prepared by known methods.
The following Reference Examples and examples illustrate the present invention, but do not limit the present invention.
In the following chemical formula, Tf represents a trifluoromethanesulfoxy group, Boc represents a t-butoxycarbonyl group, TMS represents a trimethylsilyl group, and Bn represents a benzyl group.
The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations or TLC.
The solvents in the parentheses in NMR show the solvents for measurement.